The proposed studies are aimed at a systematic investigation of endocrine physiology at the brain endothelial wall, i.e., the blood-brain barrier (BBB). Two major areas will be investigated: (i) hormone transport and (ii) hormone action. The BBB transport of the following hormones will be investigated: thyroid hormones, (T4, T3, reverse T3), steroid hormones (gonadal and adrenal0, and vitamins A and D. The role of hormone binding plasma proteins and of erythrocytes will be emphasized in studies of hormone transport. Human blood will be used in an in vivo rat brain paradigm which measures the fraction of hormone in human serum that is available for entry into brain. In addition, in vitro studieswill be performed with isolated brain capillaries and the endothelial transport of thyroid hormones and the endothelial binding of dexamethasene will be investigated. The role of tissue proteins in regulating brain uptake of hormones will also be investigated, and mathematical modeling procedures will be used. Studies of hormone action at the BBB will be aimed at elucidating the effects of insulin, thyroid hormones, ad steroid hormones, on the transport into brain of essential nutrients such as glucose, amino acids, and ketone bodies. Pathways of brain metabolism of these nutrients may be affected by precursor availability. Therefore, hormones may alter brain metabolism and function by influencing substrate supply via effects on BBB nutrient transport. The kinetic analysis of hormonal modulation of barrier transport will involve non-linear regression analysis of transport data and the determination of hormonally-induced changes in transport kinetic constants (Km, Vmax, KD). An added benefit of these studies on nutrient transport will be the application of the results to clinical studies of brain metabolism such as positron emission tomography.